3830
A. A. Camacho-D ꢀa vila
1
H NMR d: CDCl : 0.15 (s, 6H), 0.99 (s, 9H), 3.78 (s, 3H), 6.69 (1H,
3
d, J ¼ 8.4 Hz), 6.99 (d, 1H, J ¼ 1.7 Hz), 7.20 (1H, dd, J ¼ 8.4 and 1.7 Hz).
tert-Butyldimethylsilyl Ether of Combretastatin A-4 (8)
ꢀ
To an ice-cooled (ꢂ5 to 0 C) solution of the mixture of bromostyrenes 6
(
(
2.73 g, 10 mmol) and 265 mg (5 mol%) of [Fe(acac) ] in a mixture of THF
3
20 mL), and NMP (2 mL), a solution of the Grignard 7 reagent prepared
from 4.75 g (15 mmol, 1.5 equiv) of 5-bromo-2-methoxyphenol t-butyldi-
methylsilyl ether 11 and magnesium (600 mg) in THF (25 mL) was added
dropwise via syringe. After the addition, stirring continued for 30 min,
and then the reaction mixture was quenched by addition of saturated
NH Cl solution (50 mL). The phases were separated, and the aqueous
4
layer was extracted with Et O. The combined organic phases were
2
washed with brine and dried (Na SO ). Solvents were removed in vacuo,
2
4
and the residue was purified by column chromatography (SiO ) to afford
2
1
2
.63 g (61% yield) of CA-4 TBS ether 8 as an oil. H NMR d: CDCl :
3
6
.71–6.88 (m, 3H), 6.50 (s, 2H), 6.45 (d, 2H, J ¼ 12), 3.83 (s 3H), 3.78
(s, 3H), 3.70 (s, 6H), 0.93 (s, 9H), 0.05 (s, 6H).
C NMR d: CDCl : 153.1, 150.5, 144.8, 133.3, 130.25, 129.9, 128.9,
1
3
3
123.1, 121.5, 111.85, 106.07, 61.1, 56.1, 55.7, 25.9, 18.6, ꢂ4.55. IR (NaCl
neat): 3000, 2955, 2933, 2858, 2838, 1580, 1511, 1505, 1464, 1455, 1424,
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391, 1361, 1327, 1281, 1236, 1184, 1156, 1129, 1032, 1110, 995, 963,
ꢂ1
813, 784 cm . The spectral data for this compound were identical to
those reported.
[10]
Combretastatin A-4 (1)
Potassium fluoride dihydrate (1 g) was added to a solution of the silyl
ether 8 (1 g, 2.32 mmol) in methanol (10 L). The mixture was stirred under
argon. TLC monitoring of the reaction showed the disappearance of
starting material after 40 min. After this time, the mixture was diluted
with dichloromethane (10 mL) and quenched with water (10 mL). The
phases were separated, and the aqueous layer was extracted with dichlor-
omethane in three portions. The combined organic extracts were washed
with water and dried (Na SO ). Solvent removal and chromatography of
2
4
the residue on SiO (hexane=EtOAc 4:1 ! 2:1) afforded a viscous oil that
2
1
slowly solidified on standing (0.797 g, 92% yield). H NMR d: CDCl :
3
6
6
3
.92 (d, 1H, J ¼ 1.82), 6.80 (1H, dd, J ¼ 2, 8.4), 6.73 (d, 1H, J ¼ 8.4),
.52 (s, 2H), 6.44 (d, 2H, J ¼ 12), 5.51 (s, 1H, br), 3.87 (s, 3H), 3.84 (s,
H), 3.70 (s, 6H).13C NMR d: CDCl : 153.07, 146.02, 145.45, 137.34,
3